Incompatibility of industrial standards with tailor-made and niche applications

It was already noted in the Report from EuropaBio’s Industry Hearing that in the U.K, as well as in some other EU countries tissue engineering R&D takes place on a very small developmental scale in many small spin-off companies and specialist research hospitals.⁵⁹⁶ Richard Woodfield from the MHRA states that R&D of ATMPs is very strongly iterative and characterised by a gradual emergence of efficacy.⁵⁹⁷ He also pointed out that another concern, the issue of hospital production, is of particular

also Barclay, E. Stem-cell experts raise concerns about medical tourism. Lancet. 2009; Mar 14;373(9667):883-4.

591 The International Society for Stem Cell Research has recently issued Guidelines for Clinical Stem Cell Research and Clinical Translation to combat stem cell tourism. The International Society for Stem Cell Research. Guidelines for Clinical Stem Cell Research and Clinical Translation. Available at:

http://www.isscr.org/docs/default-source/guidelines/isscr-guidelines-for-stem-cell-research-and-clinical-translation.pdf?sfvrsn=2. Accessed 23 August 2016.

592 Lindvall, O., Kokaia, Z. “Towards Application of Stem Cells in Neurodegenetive Disorders” in Hug, K., Hermerén, G. (eds.), Translational Stem Cell Research. (New York, Dordrecht, Heidelberg, London:

Springer, 2011), 3-13. See also Lindvall O., Huyn I. Medical innovation and stem cell tourism. Science 2009; 324:1664-5.

593 See e.g., Lindvall, et al., op.cit., 3-13.

594 Mummery, C.”Treating Cardiac Disorders with Stem Cells” in Hug, K., Hermerén, G. (eds.), Translational Stem Cell Research. (New York, Dordrecht, Heidelberg, London: Springer), 2011, 20. See also ISSCR Guidelines for the clinical translation of stem cells. Curr Protoc Stem Cell Biol.2009;Apr;

Appendix 1; Appendix 1B. Huyn, I., Lindvall, O., Ahrlund-Richter, L., Cattaneo, R., Cavanazza-Calvo, M., Cossu, G. et al. New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell 2008; 607-9.

595 See e.g., Barclay, supra note 590.

596 EuropaBio Stakeholder Meeting Report, supra note 170, 10.

597 Ibid.

133

importance. Furthermore, he addressed the technical requirements of a tiny scale hospital production: ‘‘[c]learly these need to be risk-based and fully proportionate, to reflect the characteristics of the individual product.’’⁵⁹⁸ This particular iterative nature of R&D and risk-proportionate approaches in ATMP context will be discussed in further detail in Sections 8.2 and 8.3 of this study.

Eucomed ATMP Backgrounder raised a concern that some ATMPs that were prior to implementation of the ATMP Regulation authorised by national competent authorities in the Member States risk to be taken away from patients.⁵⁹⁹ It has been reported by Pirnay et al. that some public tissue establishments had to discontinue the production of their established therapies due to stringent regulatory requirements following from the ATMP Regulation.⁶⁰⁰ There is a problem that today some regenerative therapies are exclusively provided by the public sector under the hospital exemption. As some actors in public sector are not capable of implementing the requirements of the ATMP Regulation, valuable established therapies are risking becoming unavailable in some Member State.⁶⁰¹

Pirnay et al. mention as an example Belgian keratinocyte banks that had been supplying human keratinocytes for the treatment of burns and chronic skin wounds since 1980s to more than 1000 severely burnt patients were notified by the national competent authorities that their products are perceived as ATMPs and that the administration of these products to patients as used it to be performed (i.e. exclusively under the scope of the EUCTDs) has not been permitted after 30 December 2012. They were not allowed to continue administration of their grafts to patients despite the fact that periodic inspections by the authorities had not revealed significant quality or safety issues, which caused some established operators to exit the market.⁶⁰²

When patients are denied access to some established therapies, the ATMP Regulation risks to have a direct adverse impact on health care professionals’ ability to treat them.

As discussed above, the big pharmaceutical companies seem to have only a limited interest in investing in R&D of ATMPs. Hence, there is much hope associated with R&D activities of SMEs that are better suited to pursue niche markets. However, as mentioned, there are currently only six ATMPs on the EU market that succeeded in going through the ATMP Regulation funnel and successfully completed the mandatory centralised marketing authorisation procedure. (However, as mentioned there are currently only four ATMPs still on the market). It should be also noted that most of the ATMPs currently being developed by research units in academia and SMEs have not reached a phase of clinical trials yet, which implies a burdensome marketing authorisation process under the ATMP Regulation.⁶⁰³ Improving the availability of

598 Op.cit., 11.

599 ATMP Backgrounder, supra note 170,2. See also Pirnay et. al., supra note 22, 551.

600 Pirnay, et al., supra note 22, 553. See also Mansnérus, supra note 22, 450.

601 Pirnay, et al., supra note 22, 551. See also Mansnérus,ibid.

602 Pirnay, et al., supra note 21, 551. See also De Corte, et al., supra note 5. See also Mansnérus, supra note 22, 451.

603 Pirnay, et al., supra note 22, 551. See also Mansnérus, supra note 22, 451.

134

ATMPs to patients in the EU is predominantly, but not merely a regulatory task.⁶⁰⁴ A granted authorisation procedure does not guarantee that patients will be able to access the ATMP affordably and timely, so much work remains to be done by patient organisations and other stakeholders to lobby for access issues in the EU.⁶⁰⁵

Subsequent to the implementation of the EUCDTs the number of actors operating in the ATMP field decreased significantly due to the more stringent regulatory requirements. Now the same actors are encountering challenges with the ATMP Regulation that imposes another level of costly pharmaceutical industry standards (such as marketing authorisation and GMP requirements), irrespective of whether their tailor-made niche products reach the EU market or not. In particular, it has been criticised that these requirements have been imposed without robust scientific support (e.g., lack of evaluation of quality and safety under the EUCTDs).⁶⁰⁶ Especially, progress towards production and commercialisation of tailor-made autologous ATMPs faces considerable translational challenges under the existing regulatory framework.⁶⁰⁷ Hourd et al. point out that distinction between autologous and allogeneic therapies influences the product safety and efficacy model, as well as the approaches to manufacturing, logistics and clinical administration of the ATMP, which respectively affects the technical and regulatory requirements for development and commercialisation of safe and effective cell-based ATMPs at the required scale and cost. Among other things they have found that manufacturing and supply of more-than-minimally manipulated autologous cell-based ATMPs encounters numerous specific challenges caused by complex supply logistics and the need to scale-out production to multiple manufacturing sites or potentially near to the patient within hospital settings.⁶⁰⁸ Especially, they argue that the requirement to establish and maintain comparability risks to become under a single market authorisation an insurmountable burden for the roll-out of manufacturing processes to more than two or three sites.

The drafting history of the ATMP Regulation reveals that these mandatory requirements were created for and in close cooperation with big pharmaceutical companies, which usually manufacture large amounts of medicines to be used by vast masses of patients.⁶⁰⁹ Hourd et al. specifically note that in contrast to allogeneic therapy or traditional pharmaceuticals or biologics production, manufacturing and supply of autologous ATMPs is characterised by complicated supply logistics and the need to

604 Mush, G. Advanced therapy medicinal products: clinical trial, hospital exemption, scientific advice, marketing authorisation. State of the Art FAMHP/EMA. BVWB Annual Spring Meeting, Brussels, 29 March 2012.

605 Bignami, F., Kent, A.J., Lipucci di Paola, M., Meade, N. Participation of patients in the development of advanced therapy medicinal products. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2011;Jul;54(7):839-842.

606 See e.g. Pirnay, et al., supra note 22, 549. Pirnay, et al. refer to number of bone banks that was reduced by a third.

607 Hourd, et al, supra note 556, 1.

608 Op.cit.,7-8.

609 Pirnay, et al., supra note 22, 551. See also Mansnérus, supra note 22, 444.

135

scale-out rather than scale-up production.⁶¹⁰ Whilst it has been noted that the great majority of companies seem to pursue highly profitable business models involving mostly scalable allogeneic therapies that follow a conventional business and supply model similar to that of the conventional biopharmaceuticals.⁶¹¹ In contrast, it has been reported that as autologous ATMPs are developed in smaller quantities and they need to adapt to alternative manufacturing and distribution methods, depending on the ATMP (for instance, indication and prevalence of the disease), the method of preservation of the ATMP and the fit with the systems in place at the hospital where the ATMP will be finally administered. ⁶¹² Pearce et al. have also expressed a view that as the most of ATMPs are personalised to individual patients or produced in very small batch sizes

“[i]t is unlikely that many will fit the conventional pharmaceutical model of a single batch providing treatments for thousands of patients.”⁶¹³ A centralised marketing authorisation may provide an incentive for companies; however other actors such as hospitals, public tissue establishments and academic research units do not usually pursue marketing authorisations.⁶¹⁴ Furthermore, it has been argued that standards designed in cooperation with big pharmaceutical industry actors are not compatible with niche applications where it is hard to benefit from economies of scale, or with tailor-made single patient procedures with restricted time frames.⁶¹⁵ Both SMEs and public tissue establishments encounter this problem, as for instance GMP facilities are only profitable when manufacturing medicines on a larger industrial scale.⁶¹⁶ The DG JRC-IPTS evaluation study anticipated the current trend of concentration due to adaptation to national and EU standards will continue:

“[a]dapting to and compliance with the regulation could tie up resources that might otherwise be available for investment in R&D. This is felt to be particularly likely in the case of SMEs. As well as delaying the launch of hTEPs and limiting the range a given company develops and produces,

610 Hourd, et al, supra note 556, 5. Hourd, et al. report that Japan and South Korea have considered different regulatory evaluation approaches based on adaptive licensing or conditional marketing approvals. According to Hourd et al. these approaches are based on stepwise learning and iterative phases of data accrual and regulatory re-evaluation, which allows commercial sale in certain instances whilst pivotal trials are being conducted.

611 See also Williams, D.J., Thomas, R.J., Hourd, P.C., Chandra, A., Ratcliffe, E., Liu, Y., and Archer, J.R. Precision manufacturing for clinical-quality regenerative medicines. Philos Trans A Math Phys Eng Sci. 2012 Aug 28; 370(1973):3924-49. Foley, et al., supra note 563.

612 Hourd, et al., supra note 556,2. See also Mason, C., Dunhill, P. Assessing the value of autologous and allogeneic cells for regenerative medicine. Regenerative Medicine 2009;4(6), 835–853. McKernon, et al., supra note 557. McCall, M., Williams, D.J. What are the alternative manufacturing and supply models available to Regenerative Medicine companies and how do the finance stack up? VALUE Project Final Report, Regenerative medicine value systems: Navigating the uncertainties, 2012, 55–65. Available at:

http://www.biolatris.com/Biolatris/News & eventsfiles/VALUE%20Final%20Report.pdf. Accessed 21 June 2016.

613 Pearce, et al., supra note 540, 294.

614 Pirnay, et al., supra note 22, 549. See also Mansnérus, supra note 22, 445.

615 Apperley, F. Advanced therapies and therapeutic advance in Europe. Academic GMP—CONTRACT joint conference: the impact of EU legislation on therapeutic advance, Brussels, 11 October 2012. Pirnay, et al., supra note 22, 549. See also Mansnérus, supra note 22, 444.

616 Pirnay, et al., op.cit.,549. See also Mansnérus, op.cit., 445.

136

this could tip the scales in favour of larger firms better able to target pan-European markets. This could then lead to market consolidation in the form of takeovers or product licensing.”⁶¹⁷

In case of academia, it has been criticised that the administrative challenges GMP and GCP compliance constitutes a true hurdle for small academic manufacturers.⁶¹⁸ Open access availability of common procedures and reagent/process validations would be extremely valuable for them. It has also been reported that research funding bodies do not seem to understand the burden of paperwork relating to GMP/GCP compliance and do resource them sufficiently.

There is also a specific issue that the formal release of IMP ATMPs in the EU necessitates appointment of a qualified person. In many Member States national competent authorities approve routine pharmaceutical qualified persons for release of complex ATMPs. As many qualified persons experience that these innovative products fall outside of their general area of expertise, they are reluctant to take the risks of releasing IMP ATMPs. The ones conducting clinical trials may encounter difficulties regarding the release of IMP ATMPs. It has been reported that essential adequate training for pharmacy qualified persons in the production of ATMPs is currently lacking. The U.S. authorities do not require qualified persons for a release of IMP ATMPs. It is apparent that the evident lack of proficient qualified persons also results in substantial additional costs in ATMP production, coupled with the fact that these products are usually produced in very small quantities or even in single product batches.

The problems arising out of the mandatory qualified person requirement are stressed, as many ATMPs are tailor-made for a single patient and necessitate the final dosing right before administration. Unfortunately, a qualified person required for release of each and every single batch is tremendously expensive and sometimes logistically impossible.⁶¹⁹

In addition to the impact of the ATMP Regulation to SMEs, a concern has been expressed that due to the more stringent requirements many hospitals and tissue banks may need to abandon their ATMP efforts in the near future.⁶²⁰ Yet, Pirnay et al. predict that:

“[t]o safeguard some life-saving therapies, and because medicine won’t stop on its way, the field might evolve to circumvent legislation and find refuge under the umbrella of the ‘Declaration of Helsinki’ or the ‘single surgical procedure’ rule (e.g. peri-operative processing of cells).⁶²¹”

617 Bock, et al., supra note 77, 10.

618 Pearce, et al., supra note 540, 295.

619Ibid.

620 Pirnay, et al., supra note 22, 549. The single surgical procedure under EUCTDs is perceived as an easier opportunity to pursue medical advances, but it was found deficient in terms of some quality and safety considerations and the oversight of ATMPs manufactured and supplied by cell and tissue establishments. See also Mansnérus, supra note 22, 446.

621 Pirnay, et al., ibid. Recital 8 of Directive 2004/23/EC so-called, EUCTDs parent directive states that:

“[…]Tissues and cells used as an autologous graft (tissues removed and transplanted back to the same individual), within the same surgical procedure and without being subjected to any banking process, are also excluded from this Directive.”

137

Notwithstanding the criticism regarding the introduction of the supplementary GMP requirements for ATMPs, it has been reported that actually experienced research centres which were involved in the initial development of new ATMPs were also those who successfully achieved GMP-compliant production for clinical trials.⁶²² A study by Pearce et al. states that this connection between development success of ATMPs and translation to GMP compliant production was confirmed by an observation: those who produce know how to develop. They also noted that the centres that successfully translated to clinical trials were those that interacted actively with regulatory authorities.

It appears that either their advice is essential for successful conversion to GMP and trial or only facilities that are already skilled in GMP manufacturing or trials designs are confident enough to approach the regulatory authorities. It was also reported that some academic research centres experienced in ATMP development regularly pass GMP inspections, as they know how to comply with GMP standards and are comparable with and potentially competitive with industry actors. Many of these proficient research centres had previous experience in manufacturing nonmedical, minimally manipulated cell therapies and they have existing quality systems for compliance with national regulations and were better resourced than are purely academic laboratories developing ATMPs in isolation. In any case, it appears very difficult for new research facilities to enter the field under current regulations because of the investments required in GMP manufacturing resources. There is still a considerable a lack of GMP-compliant research centres in academia that can participate in this field of translational research.⁶²³